The chronic relapsing nature of drug abuse persists even after prolonged abstinence and is a major hurdle in curing drug abuse. Drug associated cues and contextual stimuli are clinically significant and potent triggers of relapse even in abstinent addicts. Hence the long-term goal is to understand the neurobiological substrates and molecular mechanisms underlying cue and context induced relapse of cocaine-seeking behavior. The limbic circuit mediates the rewarding and reinforcing properties of abused drugs. Repeated use of cocaine induces neuroplasticity. These alterations resemble plasticity leading to learning and memory. Changes in synaptic strength require the dynamic addition or removal of AMPA subtype of glutamate receptors and is highly regulated by neuronal activity and requires trafficking proteins. Several lines of evidence strongly suggest that synaptic plasticity resulting from AMPA receptor trafficking plays a vital role in reinstatement of cocaine seeking-behavior. GluA2-subunit of AMPA receptors is a critical AMPA receptor subunit. It controls internalization and recycling of AMPA receptors thereby regulating homeostatic plasticity. Glutamate receptor interacting protein (GRIP) and protein interacting with C-Kinase (PICK-1) specifically bind to the carboxy-terminus of GluA2 subunit of AMPA receptors and transport AMPA receptors containing this subunit. The PI has used a novel and innovative approach of microinjecting cell permeable molecular inhibitors of AMPA receptor trafficking, and has previously shown that microinjecting a peptide designed to disrupt trafficking protein-receptor interaction with AMPA receptors is sufficient to block priming induced reinstatement (J.Neuroscience 2008 and Nature Neuroscience 2008). These studies provide a strong foundation for further experimentation necessary to fully understand the role of the trafficking proteins in reinstatement of cocaine-seeking behavior. This B/START application will focus on involvement of GRIP in cue-induced reinstatement. The NAc core is important for reinstatement of cocaine-seeking precipitated by several triggers effective in promoting relapse in abstinent addicts and will be the focus of this study. Effect of intra-accumbens microinjections of a GRIP-specific peptide, TVRTYSC (Dickinson et al. 2009) or a control peptide with scrambled sequence (TVRTASC) on cue-induced reinstatement will be examined. Preliminary data is presented showing that direct microinjection of TVRTYSC into the NAc core attenuates cocaine-priming induced reinstatement. It is expected that TVRTYSC-mediated disruption of GRIP-GluA2 interaction will attenuate cue-induced reinstatement. Mechanism of peptide action will be validated. Surface expression of GluA2-containing AMPA receptors in cue-induced reinstatement will be assessed using cross-linking of surface receptors. The study of protein-protein interactions between receptors and trafficking proteins is likely to identify novel therapeutic targets for the treatment of cocaine dependence. PUBLIC HEALTH RELEVANCE: Following cocaine detoxification, the relapse rate among addicts is discouragingly high. In this application we propose to study the neurobiological mechanisms of cue-induced cocaine-seeking behavior. This will aid in identifying therapeutic strategies.